The aim of our research is to elucidate the mechanisms by which oxidative signals and oxidative stress affect physiology and disease. We focus especially on oxidative modification of specific proteins and the effect of that covalent modification on their susceptibility to degradation, especially by the proteasome. Oxidative modification is a regulated mechanism by which cells can control the degradation of specific proteins, including the iron regulatory protein 2. We have recently found that within cells there is more than one pathway for degradation of the iron regulatory protein 2, and we are working to define their characteristics. Our studies of the effect of methionine oxidation in proteins emphasize the study of transgenic and knockout mice with alterations in levels of methionine sulfoxide reductases. Our studies of purified proteasome focus on understanding the molecular characteristics which render one protein molecule a substrate while sparing another. We found that mutant superoxide dismutases which cause amyotrophic lateral sclerosis generally show increased susceptibility to the proteasome, thus generating a new hypothesis for the neurotoxicity of the mutant proteins.